Process for optically active 2-alkyl-2,5-diazabicyclo(2.2.1)heptanes

ABSTRACT

1S,4S and 1R,4R-2-Alkyl-2,5-diazabicyclo[2.2.1]heptanes useful as intermediates in the synthesis of certain antibacterial quinolones, are prepared respectively, from trans-4-hydroxy-L-proline and trans-4-hydroxy-D-proline via multistep procedures.

This is a division of application Ser. No. 07/453,365, filed on Dec. 21,1989, now U.S. Pat. No. 5,013,834, which is a continuation ofapplication Ser. No. 07/412,072, filed on Sept. 25, 1989, abandoned.

BACKGROUND OF THE INVENTION

This invention relates to the preparation of 1S,4S- and1R,4R-2-alkyl-2,5-diazabicyclo[2.2.1]heptane intermediates havingutility in the preparation of antibacterial quinolones such as thosedisclosed in U.S. Pat. No. 4,775,668.

A method for the synthesis of 2,5-diazabicyclo[2.2.1]heptanes has beendescribed by Portoghese et al., J. Org. Chem., 31, 1059 (1966).According to this method, hydroxy-L-proline is transformed intotritosylhydroxy-L-prolinol which is first reacted with benzylamine andthen with hydrogen iodide, phosphorus, and acetic acid to formN-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydroiodide. U.S. Pat. No.3,947,445 follows a similar procedure and then converts thedihydroiodide through a three step procedure into2-methyl-2,5-diazabicyclo[2.2.1]heptane.

In our prior copending application, Ser. No. 350,423, filed May 11,1989, we describe another method for the preparation of said opticallyactive 2,5-diaza-2-alkylbicyclo[2.2.1]heptanes of the formula (IX) belowfrom trans-4-hydroxy prolines of the formula (I) below.

SUMMARY OF THE INVENTION

The over-all processes of the present invention for the preparation ofoptically active 2,5-diaza-2-alkylbicyclo[2.2.1]heptanes (IX) from4-hydroxyproline (I) are shown in Schemes I and II. In these schemes,all of the compounds depicted are chiral and optically active. Viewed asformulas which depict absolute stereochemistry, they depict, forexample, trans-4-hydroxy-L-proline, also known simply as hydroxyproline,of the formula (I), and (1S,4S)-2-alkyl 2,5-diaza[2.2.1]heptanes, of theformula (IX). Viewed as formulas which depict relative stereochemistry,they also depict the corresponding enantiomers, for example,trans-4-hydroxy-D-proline (I) and(1R,4R)-2-alkyl-2,5-diaza[2.2.1]heptanes (IX). In these formulas

R, R¹ and R³ are each independently (C₁ -C₆)alkyl;

R² and R⁴ are each independently (C₁ -C₆)alkyl, trifluoromethyl or##STR1##

X and X¹ are each independently hydrogen, (C₁ -C₆)alkyl, bromo, chloro,trifluoromethyl, methoxy or nitro.

In particular, the present invention is directed to the process steps:

(VII)→(VIII) [carried out by the agency of at least one molar equivalentof an alkali metal carbonate salt in a reaction inert solvent]; ##STR2##

(VII)→(VIII)→(IX);

(I)→(II)→(III)→(IV)→(V)→(VII)→(VIII);

(XIII)→[(XIV)]→(VIII) [carried out by the agency of a hydride reducingagent in a reaction inert solvent, without isolation of the intermediateamine];

(XIII)→[(XIV)]→(VIII)→(IX); and

(I)→(X)→(XII)→(XIII)→[(XIV)]→(VIII).

The expression "reaction inert solvent" refers to a single ormulticomponent solvent, the component(s) of which do not interact withstarting materials, reagents, intermediates or products in a mannerwhich adversely affects the yield of the desired product.

In the conversion of (VII) to (VIII), the preferred reagent is K₂ CO₃and the preferred solvent is a lower alcohol, particularly methanol. Inthe conversion of (XV) to (IX), the preferred hydride reducing agent isLiAlH₄ and the preferred solvent is an ether, particularly diethyletheror tetrahydrofuran.

In these processes, the preferred values of R and R³ are each methyl; ofR¹ is methyl or ethyl; and of each of R² and R⁴ is methyl or4-methylphenyl. Because the number of steps is reduced, it is preferredthat R² and R³ or R⁴ have the same value.

The present invention is also directed to optically active intermediatesof the relative or absolute stereochemical formulas ##STR3## wherein afirst alternative,

R⁵ is (C₁ -C₆)alkyl;

R⁶ is SO₂ R² ;

R² is as defined above;

R⁷ is hydrogen or SO₂ R³ ; and

R³ is as defined above; or

in a second alternative,

R⁶ is (C₁ -C₆)alkyl;

R⁵ is SO₂ R² ;

R² is as defined above;

R⁷ is SO₂ R⁴ ; and

R⁴ is as defined above;

and ##STR4## wherein

R² and R⁴ are defined above;

R⁸ is OR¹ or NHR; and

R and R¹ are as defined above.

The preferred compounds of the formula (XV) are in the first alternativehaving R⁵ as methyl, R² as methyl or 4-methylphenyl, and, when R⁷ is SO₂R³, R³ as methyl;

and in the second alternative having R⁶ as methyl, and R² and R⁴ asmethyl or 4-methylphenyl.

The preferred compounds of the formula (XVI) have R as methyl, R¹ asmethyl or ethyl, and R² and R⁴ the same and as methyl or 4-methylphenyl.

DETAILED DESCRIPTION OF THE INVENTION

The various process steps of the present invention are readily carriedout.

The initial step according to Scheme I involves conventional reductivealkylation of a trans-hydroxyproline (I) with a (C₁ -C₆)aliphaticaldehyde or ketone appropriate to the desired N-alkyl substituent (e.g.,formaldehyde→methyl, hexanal→hexyl, acetone→isopropyl). This reductivealkylation is carried out under typical hydrogenation conditions, bestover a noble metal catalyst, preferably palladium. The catalyst can be anoble metal per se, or an oxide or salt, reduced to the active metalcatalyst under the conditions of hydrogenation, or a noble metalcatalyst on a support such as carbon or alumina. In the present instancethe most preferred catalyst is Pd/C. The reaction inert solvent includeswater, an organic solvent such as ethanol or a mixed solvent such asaqueous alcohol. When R is methyl, the preferred source of formaldehydeis simply aqueous formaldehyde and in this case water alone is thepreferred solvent. At least one molar equivalent of the aldehyde orketone is usually employed, and when this reagent (like formaldehyde) isreadily available, it can be employed in large excess in order to reducereaction time and maximize the stoichiometric yield from the generallymore valuable hydroxyproline. Temperature is not critical, temperaturesof 0°-50° C. being generally satisfactory, and ambient temperature,avoiding the cost of heating or cooling, is most preferred. Likewise,pressure is not critical, but low to moderate pressures (e.g., 1-8atmospheres) are preferred in order to avoid the need for expensive,high pressure reactors.

The second step in Scheme I (II→III) involves conventional conversion ofa carboxylic acid group to a (C₁ -C₆)carboxylate ester, preferablyaccomplished by simple strong acid catalyzed esterification with analcohol, usually employed in gross excess and also as solvent. Suitablestrong acids are such as HCl, H₂ SO₄, and R² SO₃ H where R² is definedas above, are generally employed in anhydrous or near anhydrous form inamounts ranging from truly catalytic (e.g., 10 mol %), but generally inexcess of the 100 mol % necessary to neutralize the tertiary aminegroup. Temperature is not critical, 0°-50° C. being generallysatisfactory and room temperature particularly convenient.

In the third step of Scheme I (III→IV), the lower alkyl ester group isconventionally converted to a carboxamide group by the action of ammoniain a reaction inert solvent. When water is the solvent, undiluted,concentrated ammonia is preferred. When the solvent is a lower alcoholsuch as methanol, anhydrous ammonia, saturated into the solvent, ispreferred. Temperature is not critical, 0°-50° C. being generallysatisfactory, with ambient temperatures being especially convenient.

In the fourth step of Scheme I, the carbamoyl group in (IV) is reducedwith a hydride reducing agent to the aminomethyl group in (V). Hydridereducing agents, such as diisobutyl aluminum hydride or lithium aluminumhydride which show a high level of activity in reducing amides toamines, are preferred reagents in this reduction. It is preferred to usean excess of these reagents, e.g., as many as 6 mols of diisobutylaluminum hydride or 1.5 mols of lithium aluminum hydride per mole ofamide. The reduction is carried out in a reaction inert solvent, usuallyan ether such as diethylether or tetrahydrofuran. Temperature is notcritical, 0°-50° C. generally being satisfactory and ambienttemperatures most preferred.

In Scheme I, when R² and R³ are different, the conversion of (V) to(VII) will require two steps. In the first of these, the sulfonamide isbest selectively formed by acylation of the amine with substantially onemolar equivalent of the appropriate sulfonyl chloride in the presence ofa sufficient amount of a base (such as n-butyllithium) to neutralizeco-produced hydrogen chloride, in a reaction inert solvent, suitably anether such as tetrahydrofuran. This reaction is generally carried out ata reduced temperature (e.g., -50° to +15° C.), a temperature near themiddle of this range (e.g., -10° to -15° C.), being particularlysatisfactory. In this case, subsequent O-sulfonylation (VI→VII) isreadily accomplished using at least one molar equivalent of R² SO₂ Cl inthe presence of at least one molar equivalent of a tertiary amine suchas triethylamine, generally in an aprotic solvent such as an ether(e.g., tetrahydrofuran). Temperature in this second stage is notcritical, with a temperature in the range of 0°-50° C. generallysatisfactory and ambient temperature usually preferred.

As noted above in the preferred routes R² and R³ are the same, in whichcase concurrent N- and O-sulfonylation is readily accomplished under thelatter conditions, except that at least two equivalents each of thesulfonylchloride (R³ SO₂ Cl) and the tertiary amine are employed.

At the heart of the present invention is the cyclization of thebis-sulfonylated derivative (VII) to form the 2-alkyl-5-(alkane- orbenzene-)sulfonyl derivative (VIII). This cyclization is readilyaccomplished by the agency of at least one molar equivalent of an alkalimetal carbonate (e.g., K₂ CO₃ is particularly well-suited) in a reactioninert solvent such as a lower alcohol (e.g., methanol is particularlywell-suited).

In the first step of Scheme II, the hydroxyproline (I) is converted tothe ester (X) best accomplished by the methods described above for theesterification of N-alkylhydroxyprolines (II→III). Bis-sulfonylation of(X) to form the compound of the formula (XII) and its ammonolysis to theamide (XIII) are also accomplished by the methods described above,except that the amine RNH₂ is substituted for NH₃.

However, in marked contrast to Scheme I, in Scheme II, the hydridereduction of the carbamoyl group to an alkylamino group and cyclyzationare now accomplished in a single step, viz., by the action of hydridereducing agent as described above, with the expected product, (XIV),spontaneously cyclyzing to form the desired 2-alkyl-5-alkane- orbenzenesulfonyl derivative (VIII).

Finally, in order to form the amine (IX), according to either Scheme,the N-sulfonyl group is removed by conventional reductive or hydrolyticmethods This is best accomplished with HBr in acetic acid as reagent,conveniently with isolation of (IX) in the form of its dihydrobromidesalt. Again temperature is not critical, 0°-50° C. being fullysatisfactory and ambient temperature generally preferred. Those skilledin the art will understand that sodium in liquid ammonia represents analternative reductive method for removal of the sulfonyl group, whileuse of strong aqueous acid (HCl, H₂ SO₄, etc.) represents an alternativehydrolytic method for its removal.

The starting materials required in the operation of the presentinvention are readily available. Thus, trans-hydroxy-L-proline is anatural aminoacid which is commercially available, while its enantiomeris available according to the method of Baker, et al., J. Org. Chem.,46, pp. 2954-2960 (1981).

The amines of the formula (IX) are used as the source of side chain inthe preparation of certain antibacterial quinolones such as thosedisclosed in U.S. Pat. No. 4,715,668, cited above.

The present invention is illustrated by the following Examples. However,it should be understood that the invention is not limited to thespecific details of these examples. Nomenclature used herein is based onRigaudy and Klesney, IUPAC Nomenclature of Organic Chemistry, 1979 Ed.,Pergammon Press, New York, 1979.

EXAMPLE 1 trans-N-Methyl-4-hydroxy-L-proline (II, R=CH₃)

To 40 g (305 mmol) of trans-4-hydroxy-L-proline in 80 ml of water wasadded 80 ml of 30% aqueous formaldehyde solution and 7.0 g of 5%palladium on carbon catalyst (50% wet), and the mixture was hydrogenatedat 50 psig using a Parr Shaker. After 24 hours, the catalyst wasrecovered by filtration over diatomaceous earth and the filtrateevaporated under reduced pressure to provide 43.5 g (98.3%) of titleproduct; mp 140°-142° C. (decomposition); ¹ H-NMR (D₂ O) 4.65 (m, 1H),4.20 (dd, 1H), 3.97 (dd, 1H), 3.2 (dm, 1H), 2.50 (m, 1H), 2.25 (m, 1H);[alpha]_(D) =-54.8° (c=1.18, H₂ O).

By the same method, trans-4-hydroxy-D-proline is converted to enantiomectrans-N-methyl-4-hydroxy-D-proline, having identical properties exceptfor sign of rotation.

EXAMPLE 2 trans-N-Methyl-4-hydroxy-L-proline Methyl Ester (III, R=R¹=CH₃)

Title product of the preceding Example (100 g, 690 mmol) was suspendedin 600 ml of methanol and anhydrous HCl gas was bubbled through thereaction mixture until it became homogeneous. The reaction was thenheated to reflux for 16 hours, after which it was cooled and the solventwas replaced with 150 ml of water. 200 g (1.44 mol) of potassiumcarbonate was then added carefully at 0° C. and the product wasextracted with 4×200 ml portions of ethyl acetate. The combined organiclayers were dried (Na₂ SO₄) and evaporated to provide 87 g (72%) ofproduct as a white solid; mp 53°-54° C.; ¹ H-NMR(D₂ O) 4.85 (s, 3H),4.73 (m, 2H), 3.90 (s, 3H, N-methyl), 3.58 (m, 1H), 3.45 (m, 1H), 2.54(m, 1H), 2.37 (m, 1H); [alpha]_(D) =-80.0° (c=1.038, CH₃ OH).

By the same method, the enantiomeric product of the preceding Example isconverted to the enantiomer of present title product, having identicalproperties except for sign of rotation.

EXAMPLE 3 (2S,4R)-1-Methyl-2-carbamoyl-4-hydroxypyrrolidine (IV, R=CH₃)

Title product of the preceding Example (20 g, 126 mmol) was dissolved in40 ml of ice cold, saturated NH₄ OH, and the resulting solution thenwarmed to room temperature. After stirring for 24 hours the solvent wasremoved under high vacuum to produce a quantitive yield of present titleproduct as a white, crystalline solid; mp 138°-140° C.; Anal. C 49.99, H8.40, N 18.27; calcd. C 49.97, H 8.40, N 19.43; ¹ H-NMR (D₂ O) 4.43 (m,1H), 3.42 (dd, 1H), 3.25 (AB pattern, 1H), 2.36 (s, H), 2.33 (M, 1H),2.1 (m, 2H); [alpha]_(D) =-105.48° (c=0.953, CH₃ OH).

By the same method, the enantiomeric product of the preceding Example isconverted to the enantiomer of present title product, having identicalproperties except for sign of rotation.

EXAMPLE 4 (2S,4R)-1-Methyl-2-aminomethyl-4-hydroxypyrrolidine (V, R=CH₃)

Title product of the preceding Example (15 g, 104 mmol) was suspended in75 ml of tetrahydrofuran and 572.5 ml (572.5 mmol) of diisobutylaluminum hydride (1M solution in hexanes) was added over a period of 15minutes. The mixture was then heated to reflux for two days and judgedcomplete by monitoring with thin layer chromatography. Diatomaceousearth (30 g) was then added to the reaction and while cooling with anice bath, 300 ml of methanol was added dropwise. The slurry was thenfiltered and the solvents were evaporated to provide 8.1 g of acolorless oily product (60%); ¹³ C-NMR (D₂ O) 69.5 (CH), 66.8 (CH), 64.9(CH₂), 44.0 (CH₂), 41.0 (CH₃), 39.5 (CH₂); [alpha]_(D) =-61.94°(c=0.956, CH₃ OH).

By the same method, the enantiomeric product of the preceding Example isconverted to the enantomer of present title product, having identicalproperties except for sign of rotation.

EXAMPLE 5

(2S,4R)-1-Methyl-2-[(4-methylbenzenesulfonylamino)methyl]-4-hydroxypyrrolidine(VI, R=CH₃, R² =p-CH₃ C₆ H₄)

To title product of the preceding Example (7.3 g, 56.2 mmol) in 200 mlof tetrahydrofuran at -10° C. was added 22.46 ml of n-butyllithium (56.2mmol, 2.5M in hexanes) over a period of 30 minutes. p-Toluenesulfonylchloride (10.2 g, 53.3 mmol) in 10 ml of tetrahydrofuran was then added.After stirring the mixture for two hours at -10° C., 20 ml of water wereadded and the reaction was extracted with 2×140 ml of methylenechloride. The combined organic layers were dried (Na₂ SO₄) andevaporated at reduced pressure to provide 15 g (94.3%) of present titleproduct as a light yellow oil; ¹³ C-NMR (CDCl₃) 143.4, 136.5, 129.7,127.0, 69.1, 64.7, 62.4, 43.0, 40.0, 38.2, 21.5; [alpha]_(D) =-34.67°(c=0.90, CH₃ OH).

EXAMPLE 6(2S,4R)-1-Methyl-2-[(4-methylbenzensulfonylamino)methyl]-4-(methanesulfonyloxy)pyrrolidine(VII, R=R³ =CH₃, R² =pCH₃ C₆ H₄)

To title product of the preceding Example (1.0 g, 3.5 mmol) in 20 ml oftetrahydrofuran was added 0.49 ml (3.5 mmol) of triethylamine and 0.27ml (3.5 mmol) of methanesulfonyl chloride. After stirring at roomtemperature for 30 minutes, 20 ml of water were added and the reactionwas extracted with 2×40 ml of methylene chloride. The combined organiclayers were then dried (Na₂ SO₄) and evaporated under reduced pressureto provide 1.2 g (94%) of product as an oil; ¹ H-NMR (CDCl₃) 7.73 (d,2H), 7.40 (d, 2H), 5.04 (m, 1H), 3.70 (m, 1H), 3.55 (dd, 1H), 3.05 (m,1H), 3.0 (s, 3H), 2.83 (m, 1H), 2.62 (dd, 1H), 2.40 (s, 3H), 2.23 (s,3H), 2.10 (m, 1H), 1.82 (m, 1H).

EXAMPLE 7(2S,4R)-1-Methyl-2-[(methanesulfonylamino)methyl]-4-methanesulfonyloxypyrrolidine(VII, R=R² =R³ =CH₃)

To title product of Example 4 (100 mg, 0.76 mmol) in 2 ml oftetrahydrofuran was added 0.21 ml (1.52 mmol) of triethylamine and 0.118ml (1.52 mmol) of methanesulfonyl chloride and the mixture was allowedto stir at 0° C. for one hour and at room temperature for an additionalhour. Then 2 ml of water were added and the mixture was extracted with2×2 ml of methylene chloride. The combined organic layers were dried(MgSO₄) and evaporated under reduced pressure to provide 140 mg (64%) ofpresent title product as an oil; ¹ H-NMR (CDCl₃) 5.05 (m, 1H), 3.50 (dd,1H), 3.17 (m, 1H), 3.0 (s, 3H), 2.95 (s, 3H), 2.80 (m, 1H), 2.58 (dd,1H), 2.30 (s, 3H), 2.25-2.1 (m, 3H). CMR(CDCl₃): 78.4, 62.3, 61.9, 42.5,40.1, 39.8, 38.2, 35.4. MS: M+1 287(20), 191(17), 178(100).

By the same method, the enantiomeric product of Example 4 is convertedto(2R,4S)-1-methyl-2-[(methanesulfonylamino)methyl]-4-methanesulfonyloxypyrrolidine.

EXAMPLE 8(1S,4S)-2-Methyl-5-(4-methylbenzenesulfonyl)-2,5-diazabicyclo[2.2.1]heptane(VIII, R=CH₃, R² =pCH₃ C₆ H₄)

To title product of Example 6 (760 mg, 5.52 mmol) was added 760 mg (5.52mmol) of K₂ CO₃. After stirring the mixture for 24 hours, the solventwas removed under reduced pressure and 20 ml of water were added. Theaqueous layer was then extracted with 2×40 ml of methylene chloride andthe combined organic layers were dried (MgSO₄) and evaporated underreduced pressure to provide 470 mg (64%) of present title product as asolid; mp 87°-88° C.; 13C-NMR (CDCl₃) 143.5, 135.4, 129.8, 127.4, 62.9,61.1, 61.0, 49.9, 40.2, 34.9, Anal. C 58.73, H 6.90, N 10.51, S 12.26,calcd. C 58.62, H 6.81, N 10.52, S 12.04; [alpha]_(D) =+18.69° (c=1.18,CH₃ OH).

EXAMPLE 9(1S,4S)-2-(Methanesulfonyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane(VIII, R=R² =CH₃)

By the method of the preceding Example, title product of Example 7 (110mg, 0.38 mmol) was converted to present title product as an oil,purified by chromatography on silica gel; 44 mg (60%); ¹ H-NMR (CDCl₃)4.27 (m, 1H), 3.55 (dd, 1H), 3.5 (s, 3H), 3.20 (dd, 1H), 2.84 (m, 3H),1.92 (m, 1H), 1.71 (m, 1H); ¹³ C-NMR (CDCl₃): 63.1, 61.4, 60.6, 50.6,40.8, 38.5, 35.7.

By the same method, the enantiomeric product of Example 7 is convertedto (1R,4R)-2-(methanesulfonyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane.

EXAMPLE 10 (1S,4S)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane (IX, R=CH₃)

Title product of Example 8 (60 g, 225 mmol) was suspended in 900 ml of30% HBr in CH₃ COOH, stirred for six hours at room temperature, thenreduced to 1/4 volume at the water aspirator, the residue diluted with1800 ml of ethyl acetate, and the resulting precipitated solidsrecovered by filtration. These solids were recrystallized by dissolvingin the minimum necessary CH₃ OH at reflux, cooling and the addition of400 ml of isopropyl alcohol to yield 48 g (81%) of present, purifiedtitle product; mp 258°-259° C.; ¹ H-NMR (D₂ O) 4.73 (m, 1H), 4.62 (m,1H), 3.8-3.6 (m, 4H), 3.08 (s, 3H), 2.65 (m, 1H), 2.35 (m, 1H);[alpha]_(D) =+13.21° (c=0.946, CH₃ OH).

By the same method, the title product of Example 9 is also converted topresent title product, and the enantiomeric product of Example 9 isconverted to (1R,1R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane.

EXAMPLE 11 trans-4-Hydroxy-L-proline Methyl Ester Hydrochloride (X, R¹=CH₃)

Anhydrous HCl was bubbled through a stirred suspension oftrans-4-hydroxy-L-proline (80 g, 0.61 mol) in 500 ml anhydrous methanoluntil the mixture was homogeneous. The reaction was heated to reflux forfive hours, and the volume of the solvent then reduced by one half.Ether (100 ml) was added, and the mixture kept in a freezer overnight.The resulting precipitate was filtered, washed with ether and driedunder reduced pressure to yield 111 g of present title product (93%yield). mp 170°-172° C.

By the same method, trans-4-hydroxy-D-proline is converted to theenantiomer of present title product.

EXAMPLE 12 Methyl(2S,4R)-1-(4-Methylbenzenesulfonyl)-4-(4-methylbenzenesulfonyloxy)pyrrolidine-2-carboxylate(XII, R¹ =CH₃, R² =R⁴ =CH₃ C₆ H₄)

Title product of the preceding Example (15 g, 83.1 mmol) was stirredwith 150 ml pyridine and 11.5 ml of triethylamine at 0° C. for 30minutes. p-Toluenesulfonyl chloride (34.8 g, 181.9 mmol) was addedportionwise, maintaining a temperature of 0°-5° C. The mixture wasstirred 18 hours at 0° C., then added to two volumes of ice cold water,stirred at room temperature for one hour, and present title productrecovered by filtration and dried in vacuo at 30° C. for 48 hours toyield 38 g (99%) of present title product, mp 94°-95° C.

By the same method, the enantomeric product of the preceding Example isconverted to the enantiomer of present title product.

Substituting methanesulfonyl chloride for p-toluenesulfonyl chloride,the same method is used to prepare methyl(2S,4S)-1-methanesulfonyl-4-methanesulfonyloxypyrrolidine-2-carboxylate.

EXAMPLE 13(2S,4S)-N2-Methyl-1-(4-methylbenzenesulfonyl)-4-(4-methylbenzenesulfonyloxy)pyrrolidine-2-carboxamide(XIII, R=CH₃, R² =R⁴ =CH₃ C₆ H₄)

Water (400 ml) was saturated with methylamine gas (20 minutes). Titleproduct of the preceding Example (41 g, 89.4 mmol) was added and theresulting slurry stirred for 6 days. Present title product (25.2 g, 62%)was recovered as a white solid by filtration, mp 147°-149° C.;[alpha]_(D) ²⁵ =-80.70 (c=1.108, methanol);

Anal. C 53.25, H 5.24, N 6.05, calcd. C 53.08, H 5.35, N 6.19.

By the same method, the enantiomeric product of the preceding Example isconverted to the enantiomer of present title product, and thebis-methanesulfonyl analog of the preceding Example is converted to(2S,4S)-N²-methyl-1-methanesulfonyl-4-methanesulfonyloxypyrrolidine-2-carboxamide.

EXAMPLE 14(1S,4S)-2-Methyl-5-(4-methylbenzenesulfonyl)-2,5-diazabicyclo[2.2.1]heptane(VIII, R=CH₃, R² =CH₃ C₆ H₄)

To title product of the preceding Example (2.0 g, 4.42 mmol) in 20 mltetrahydrofuran was added LiAlH₄ (750 mg, 19.9 mmol). The reactionmixture was stirred 24 hours, then quenched by the addition of 3 ml H₂ Oand 0.75 ml 15% NaOH and extracted 2×15 ml CH₂ Cl₂. The combinedextracts were dried (MgSO₄) and stripped to yield 1 g (85%) of titleproduct as a white solid identical with the product of Example 8.

By the same method, the enantiomeric product of the preceding Example isconverted to(1R,4R)-2-methyl-5-(4-methylbenzenesulfonyl)-2,5-diazabicyclo[2.2.1]heptane,having identical physical properties except for sign of rotation; andthe bis-methanesulfonyl analog of the preceding Example is converted to(1S,4S)-2-methanesulfonyl-5-methyl-2,5-diazabicyclo[2.2.1]heptane,identical in physical properties with the product of Example 9.

We claim:
 1. A process for the preparation of an optically active2,5-diazabicyclo[2.2.1]heptane of the relative or absolutestereochemical formula ##STR5## wherein R is (C₁ -C₆)alkyl; R² is (C₁-C₆)alkyl trifluoromethyl or ##STR6## and X and X¹ are eachindependently hydrogen, (C₁ -C₆)alkyl, bromo, chloro, trifluoromethyl,methoxy or nitro; which comprises the steps of:(a) reductive alkylationof an optically active hydroxyproline of the relative or absolutestereochemical formula ##STR7## to form an N-alkylhydroxyproline of theformula ##STR8## (b) esterification of said N-alkylhydroxyproline withan alcohol of the formula

    R.sup.1 OH,

wherein R¹ is (C₁ -C₆)alkyl, in the presence of an acid catalyst to forman ester of the formula ##STR9## (c) ammonolysis of said ester with NH₃to form an amide of the formula ##STR10## (d) hydride reduction of saidamide to form an aminomethyl derivative of the formula ##STR11## (e)stepwise N-sulfonylation followed by O-sulfonylation of said aminomethylderivative to form a sulfonamide of the formula ##STR12## wherein R³ isas defined above and R³ is (C₁ -C₆)alkyl, or concurrent N- andO-sulfonylation to form a sulfonamide of the formula (VII) wherein R² islimited to (C₁ -C₆)alkyl and R² R³ each have the same value; (f)contacting said sulfonamide with at least one molar equivalent of analkali metal carbonate in a reaction inert solvent until the conversionof said sulfonamide to said compound of the formula (VIII) issubstantially complete
 2. A process of claim 1 for a2,5-diazabicyclo[2.2.1]heptane of the absolute stereochemical formula(VIII).
 3. A process of claim 1 wherein R is methyl.
 4. A process ofclaim 2 wherein R is methyl.
 5. A process of claim 16 wherein R² ismethyl or 4-methylphenyl and R³ is methyl.
 6. A process of claim 4wherein R² is methyl or 4-methylphenyl and R³ is methyl.
 7. A process ofclaim 1 wherein the alkali metal carbonate is K₂ CO₃ and the solvent ismethanol.
 8. A process of claim 2 wherein the alkali metal carbonate isK₂ CO₃ and the solvent is methanol.
 9. A process of claim 6 wherein thealkali metal carbonate is K₂ CO₃ and the solvent is methanol.
 10. Aprocess of claim 1 which further comprises removal of the R² SO₂ -groupfrom said compound of the formula (VIII) by reaction with HBr in aceticacid to form an optically active compound of the relative or absolutestereochemical formula ##STR13##
 11. A process of claim 10 for acompound of the absolute stereochemical formula (IX).
 12. A process ofclaim 10 wherein R is methyl and R² is methyl or 4-methylphenyl.
 13. Aprocess of claim 11 wherein R is methyl and R² is methyl or4-methylphenyl.